Essential oil–cyclodextrin complexes: an updated review

Cyclodextrins, degradation product of carbohydrates, have been extensively exploited by food, pharmaceutical and cosmetic industry by virtue of their ease of availability and their ability to entrap guest moieties. Various cyclodextrin derivatives have been granted generally recognized as safe (GRAS) status by several countries. The most noteworthy characteristic of cyclodextrins is their ability to form inclusion complexes with variety of molecules, imparting protection and enabling solubility, bioavailability and safety enhancement of challenging bioactives. In the last few decades, investigations have revealed anti-microbial, anti-inflammatory, insecticidal, analgesic and sedative properties of essential oils. However, their poor solubility, volatility and sensitivity to environmental factors pose challenge for the formulation scientists. Inclusion complexes of essential oils with cyclodextrins have proved a useful strategy to circumvent these challenges. The success of this approach for essential oils is examplified by the commercial garlic oil/β-cyclodextrin products, available under the trade names Xund, Tegra, Allidex and Garlessence. Here, we present an in-depth account of essential oil loaded cyclodextrin inclusion complexes.     

Solubilization of itraconazole as a function of cyclodextrin structural space

Cyclodextrins are functional pharmaceutical excipients, which can dynamically include poorly water-soluble drugs and drug candidates resulting in improved solubility, stability and oral bioavailability. A number of formulations containing “natural” and chemically modified cyclodextrins have reached the market and are enjoying widespread attention and use. One such example is itraconazole, a broad-spectrum antifungal agent which is available in an aqueous hydroxypropyl-β-cyclodextrin (HPβCD) vehicle for both oral and parenteral use (Sporanox Oral Solution and Sporanox Intravenous Injection^®). While the interaction of itraconazole and HPβCD is well described, its ability to form complexes with other cyclodextrins is less understood. This creates an intriguing opportunity of screening the structural space of available cyclodextrin derivates by assessing their complexation with a single chemical probe, in this case itraconazole. To this end, a number of cyclodextrin derivatives were assess with regard to their ability to improve the water solubility of the test substrate. In some instances, more detail assessments including the effect of pH and the physical form of the drug probe were also completed. The various cyclodextrins solubilized itraconazole to varying extents (micrograms to milligrams) and by varying inclusion mechanisms and stoichiometries.     

环糊精及其衍生物在手性识别中的应用

详细地论述了环糊精及其衍生物在手性识别中的应用,并对环糊精超分子体系手性识别中的进一步研究提供了依据。     

The complexation efficiency

Studies have shown that cyclodextrins form both inclusion and non-inclusion complexes and that several different types of complexes can coexist in aqueous solutions. In addition, both cyclodextrins and cyclodextrin complexes are known to form aggregates and it is thought that these aggregates are able to solubilize drugs through micellar-type mechanism. Thus, stability constants determined from phase-solubility profiles are rarely true stability constants for of some specific drug/cyclodextrin complexes. A more precise method for evaluation of the solubilizing effects of cyclodextrins is to determine their complexation efficiency (CE). CE can be determined by measuring the solubility of a given drug at 2–3 cyclodextrin concentrations in pure water or a medium constituting the pharmaceutical formulation such as parenteral solution or aqueous eye drop formulation. Based on the CE value the drug:cyclodextrin ratio in the complexation medium can be determined as well as the increase in the formulation bulk in a solid dosage form. Determination of CE is a simple method for quick evaluating the solubilizing effects of different cyclodextrins and/or the effects of excipients on the solubilization. Here we report the CE of 43 different drugs with mainly 2-hydroxypropyl-β-cyclodextrin but also with randomly methylated β-cyclodextrin as well as few other cyclodextrins. Calculation of CE, drug:cyclodextrin molar ratio and the increase in the formulation bulk is discussed, as well as the influence of the intrinsic solubility and drug lipophilicity on the CE.     

Cyclodextrins and the Biopharmaceutics Classification System of Drugs

Although the biopharmaceutics classification system (BCS) was originally developed for solid oral dosage forms this system can be extended to other types of drug delivery forms. According to the BCS aqueous solubility and permeability are the most important parameters affecting drug bioavailability. Cyclodextrins can enhance the aqueous solubility of lipophilic drugs without changing their intrinsic ability to permeate biological membranes. Thus, through cyclodextrin complexation it is possible to move Class II drugs, and sometimes even Class IV drugs, into Class I. However, cyclodextrins can decrease bioavailability of Class I drugs and will in most cases not improve bioavailability of Class III drugs. Through formation of drug/cyclodextrin/polymer ternary complexes it is possible to enhance the complexation efficacy of cyclodextrins and at the same time improve drug bioavailability from cyclodextrin containing drug formulations.     

含氮基团修饰β-环糊精量子化学研究

用PM3半经验方法优化了5种不同含氮基团修饰环糊精的结构,并用HF方法在STO-3G和3-21G*两种基组水平上计算了它们的单点能.首次给出了这5种修饰环糊精的优化结构,同时计算结果采用极性基团会增加修饰环糊精的偶极距,优化的结构及计算出的物理性质表明修饰后产物明显与β-环糊精有明显的差别.     

Cyclodextrin knowledgebase a web-based service managing CD-ligand complexation data

Cyclodextrins are cyclic oligosaccharides that are able to form water-soluble inclusion complexes with small molecules. Because of their complexing ability, they are widely applied in food, pharmaceutical and chemical industries. In this paper we describe the development of a free web-service, Cyclodextrin KnowledgeBase: (http://www.cyclodextrin.net). The database contains four modules: the Publication, Interaction, Chirality and Analysis Modules. In the Publication Module, almost 50,000 publication details are collected that can be retrieved by text search. In the Interaction and Chirality Modules relevant literature data on cyclodextrin complexation and chiral recognition are collected that can be retrieved by both text and structural searches. Moreover, in the Analysis Module, the geometries of small molecule-cyclodextrin complexes can be predicted using molecular docking tools in order to explore the structures and interaction energies of the inclusion complexes. Complex geometry prediction is made possible by the built-in database of 95 cyclodextrin derivatives, where the 3D structures as well as the partial charges are calculated and stored for further utilization. The use of the database is demonstrated by several examples.     

Syntheses Characterization of Chloro-cyclopentadienyltricarbonyl-molybdenum with β-Cyclodextrin Supramolecular

Organotransition metal complex have been extensively used as homogeneous catalysts in organic reactions and much effort has been paid to improve their activity and selectively. Cyclodextrins have been studied as a model of enzyme for selective catalysis. However, so far there are only a few reports on the inclusion compounds of organometallic complexes with cyclodextrins. Breslow et al.repored high acylation rates for β-CD using ferrocene derivatives and assumed β-CD substrate complexes as intermediate [1]..larad et al reported the preparation and propertics of cyclodextrin-ferrocen inclusion compounds as the first example of cyclodextrin inclusion compounds of organotransition metal complexes[2]. Song Le-Xin et al reported the supramolecular inclusion compound of β-cyclodextrin with cyclopentadieny-tricarbonylmanganese [3] .To our knowledge, there are no reports of inclusion compounds of β-CD with molybdenum organometallic complexes. In the present work we described the preparation and properties of the supramolecular of CpMo(CO)3Cl with β-CD in details.     

环糊精及其衍生物在环境污染物治理中的应用

环糊精是由不同的D-吡喃葡萄糖单元环状排列而成的圆锥状中空桶形分子,其独特的外亲水内疏水结构决定了其特殊的性能。目前环糊精及其衍生物在药剂学中的应用最为广泛,而在环境污染物治理方面的报道较少。本文介绍了环糊精主-客体包合作用影响因素、环糊精衍生物的合成方法,综述了近年来环糊精及其衍生物在污染水、土壤及大气治理中的研究进展,表明其在环境污染治理方面有较好的应用前景,并提出了其在环境污染物治理中未来的研究方向。     

Supramolecular assemblies through macromolecular recognition by cyclodextrins

Cyclodextrins have been found to form inclusion complexes with various polymers with high specificities to give stoichiometric compounds in crystalline states. Polyrotaxanes in which many cyclodextrins are threaded on a single chain were prepared by capping the chain ends with bulky groups.     

环糊精高分子

环糊精以其独特的包合特性而引入注目，已被广泛地应用于化学分离及分析、药物控制释放、食品加工和环境保护等领域。环糊精高分子亦被证实具有包含、缓释及催化的能力，以及良好的机械强度和化学稳定性。本文综述了国内外关于环糊精高分子的类型、合成方法及实际应用的最新研究进展。     

Bile pigment complexes with cyclodextrins: electronic and vibrational circular dichroism study

Chiral recognition of bilirubin IX-α, biliverdin IX-α, and bilirubin ditaurate dianions by cyclodextrins was studied using a combination of vibrational and electronic circular dichroism. Biliverdin forms inclusion complexes with β-cyclodextrin and β-methylcyclodextrin. Bilirubin bonds to both cyclodextrins by means of hydrogen bonds and only shallow inclusions that are restricted by the presence of COO⁻ in the pigment structure. Bilirubin ditaurate complexes are realized by a weak inclusion of the whole molecule, or some part of it, into the cyclodextrin cavity and stabilization of the conformation by hydrogen bonds. Bilirubin and bilirubin ditaurate can be recognized by cyclodextrin and methylcyclodextrin in the form of opposite conformers. Spectroscopic characteristics of the different conformations of the bile pigments were obtained for the first time by vibrational circular dichroism techniques.     

Binding behaviors of scutellarin with α-, β-, γ-cyclodextrins and their derivatives

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, ¹H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.     

Study on the supramolecular system of TAPP with cyclodextrins by polarography

The interaction of cyclodextrins with meso- Tetrakis (4-N-trimethylaminobenzyl) porphyrin (TAPP) in 0.1 mol l(-1) phosphate buffer (pH 7.0, 20 degrees C) has been studied by polarography. The TAPP can form the 1:1 inclusion complex with Sulfobutylether-beta-cyclodextrin (SBE-beta-CD) and1:2 inclusion complexes with other four cyclodextrins. A new expression, which is used to calculate the inclusion constant for1:2 inclusion complex by polarography, has been educed and testified firstly in this paper. Furthermore, the inclusion abilities of different kinds of cyclodextrins are compared. The result shows the inclusion ability of anionic cyclodextrin SBE-beta-CD with cationic porphyrin TAPP is very strong. It suggests that the charge attraction between CDs and TAPP plays an important role in the inclusion procedure except for the hydrophobic effect. The inclusion formation of anionic cyclodextrins with drugs can increase released rate of drugs at high pH; therefore, the suparmolecular data for the controlled release of the drugs that owned the similar properties as hematoporphyrin have been offered by polarography in this paper.     

利用人工模拟酶环糊精催化羧酸酯水解反应的研究进展

环糊精因其结构和性质的特殊性在人工模拟酶方面发挥着重要的作用．概述了 利用简单的环糊精、带有催化基团的环糊精和二聚体环糊精催化羧酸酯水解反应的 研究进展．     

环糊精作为纳米反应器催化的有机反应

环糊精是由六、七或八个D-吡喃葡萄糖单元通过a-1,4糖苷键连接成的环状低聚糖, 由于其特殊的结构使其在水溶液中可以复合包结系列底物. 这个特殊的性能使其在模拟酶及催化等许多领域有着广阔的应用, 特别适合作为一种纳米级的反应器来使用. 概述了近几年环糊精及其衍生物作为有机反应纳米反应器的功能特点.     

Cyclodextrins in Eye Drop Formulations

Ideally, eye drop formulations are aqueous solutions. Many drugs that are useful in topical application to the eye are not sufficiently water soluble to be dissolved in simple aqueous solutions. This problem is approached through hydrophilic prodrugs, suspensions, lipid based solutions and excipients such as cyclodextrins. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various ophthalmic drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine and cyclosporins. Their use in ophthalmology has already begun and it is likely to expand the selection of drugs available as eye drops. In this paper we review the use of cyclodextrins in eye drop formulations. The use of cyclodextrins to formulate dexamethasone eye drops is an example of their usefulness. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with concentration and ocular absorption, which in human and animal studies is many fold that seen with presently available formulations. Such formulations offer the possibility of once a day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation.     

Cyclodextrins and the liquid-liquid phase distribution of progesterone, estrone and prednicarbate

The purpose of the present work was to investigate the interaction of drugs and octanol with hydroxypropyl β- (HPβCD) and γ- (HPγCD) cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD) and randomly methylated-β-cycoldextrin (RMβCD) and to describe the interaction by theoretical models. The poorly soluble steroid drugs progesterone, estrone and prednicarbate were used as model compounds in this study. Hexane and chloroform were also investigated in combination with HPβCD. Octanol formed a complex with all cyclodextrins and the saturation of the aqueous solution with this solvent therefore had a significant effect on the solubilization and extraction potential of cyclodextrins. Hexane had less affinity for cyclodextrins, but the drugs were poorly soluble in this solvent and it could therefore not be used in phase-distribution investigations. Previously we have derived equations that can be used to account for the competitive interaction between two guest compounds that compete for space in the cyclodextrin cavity. These equations were rearranged to calculate the complexation efficacy from phase-solubility data. An equation was derived that obtains intrinsic solubility (S ₀) and intrinsic partition coefficient (P) from the slopes of the phase-solubility and phase-distribution profiles. Investigation of the data showed that the results could not be sufficiently explained by the “classical” drug/cyclodextrin complex model that recognizes the possibility of competitive interactions but ignores any contribution from higher order complexes or aggregation of the cyclodextrin complexes. Relative difference in solubilization potential of different cyclodextrins cannot be translated to relative differences in extraction efficacy. Thus, for these three steroid compounds, RMβCD and SBEβCD gave the best solubilization potential whereas the best extraction efficacy was observed with HPγCD.     

Complexation of morin with three kinds of cyclodextrin. A thermodynamic and reactivity study

Properties of inclusion complexes between morin (M) and beta-cyclodextrin (betaCD), 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and Heptakis (2,6-O-di methyl) beta-cyclodextrin (DMbetaCD) such as aqueous solubility and the association constants of this complex have been determined. The water solubility of morin was increased by inclusion with cyclodextrins. The phase-solubility diagrams drawn from UV spectral measurements are of the A(L)-type. Also ORAC(FL) studies were done. An increase in the antioxidant reactivity is observed when morin form inclusion complex with the three cyclodextrin studied. Finally, thermodynamics studies of cyclodextrin complexes indicated that for DMbetaCD the inclusion is primarily enthalpy-driven process meanwhile betaCD and HPbetaCD are entropy-driven processes. This is corroborated by the different inclusion geometries obtained by 2D-NMR.     

Cyclodextrins as carriers for cinchona alkaloids: a pH-responsive selective binding system

A series of cyclodextrin-cinchona alkaloid inclusion complexes were prepared from beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and four cinchona alkaloids in ca. 90% yields, and their inclusion complexation behavior was investigated at pH 7.2 and 1.5 by means of fluorescence, UV/Vis and 2D NMR spectroscopy. The results showed that the cinchona alkaloids can be efficiently encapsulated in the cyclodextrin cavity in an acidic environment and sufficiently released in a neutral environment, which makes these cyclodextrin derivatives the potential carriers for cinchona alkaloids. The binding ability and molecular selectivity of cyclodextrins toward cinchona alkaloids were discussed from the viewpoint of the size-fit concept and multiple recognition mechanism between host and guest.